Chronic kidney disease (CKD) is a growing public health problem that affects more than 10% of Veterans, increases morbidity and mortality, and imposes a huge economic burden. Persistent renal tubular injury is an important component of tubulointerstitial fibrosis (TIF), the common feature of progressive CKD of any etiology. Growth factors such as transforming growth factor-? (TGF-?) and Wnt/?-catenin are important determinants of how tubular epithelia respond to injury. Various inhibitors of the Wnt/?-catenin pathway have had mixed effects on chronic renal injury. We used a genetic approach to augment ?-catenin signaling in the proximal tubule, and this resulted in marked improvement in CKD progression after renal injury. Wnt/?-catenin signaling mediates very different actions in injury versus homeostasis. Our preliminary data suggest that ?-catenin binding to the transcription factor FoxO may be an important mediator of the altered ?-catenin-dependent responses in injury. This proposal tests the hypothesis that epithelial ?-catenin signaling protects against CKD progression by protective effects on inflammation, oxidative stress, and cell cycle progression in a manner partly dependent on FoxO. The first aim investigates how epithelial ?-catenin signaling alters epithelial survival through effects on inflammation, cell cycle, and antioxidant production using murine models of injury. We will use genetically modified mice that have a mutation in ?-catenin that prevents its degradation, and this mutant ?-catenin is either specifically expressed in the proximal tubule or present throughout the tubule in a doxycycline-inducible manner. We will induce chronic kidney injury by either angiotensin/uninephrectomy or aristolochic acid. We anticipate that mice with increased epithelial ?-catenin activity have reduced inflammation, altered cell cycle progression, reduced oxidative stress, and increased epithelial survival after injury. We have identified a number of potential ?-catenin targets that may mediate these effects based on our preliminary data. We will measure expression of these targets in the injured animal models and test how they affect cell death using cell culture techniques. The second aim explores the role of FoxO in mediating ?-catenin's protective effect after chronic kidney injury. We will determine how injury (i.e. oxidative stress) alters the way ?-catenin signals to promote FoxO- mediated responses using a special reporter mouse. We will also cross our mouse containing the active ?- catenin in the proximal tubule with our mouse lacking FoxO in the same epithelial segment. If the benefit of ?- catenin activity is mediated through FoxO, then this double conditional knockout mouse should lose the protective effect (i.e. more epithelial cell death) conferred by augmented ?-catenin activity. Furthermore, we will define how FoxO targets change epithelial responses to stress using cell culture techniques. This proposal uses innovative genetic approaches to determine the role of ?-catenin and FoxO interactions in epithelial injury. We will investigate several novel targets of these protein interactions identified by sequencing the transcriptome (preliminary data). These studies will provide valuable pre-clinical data for these targets which may lead to future therapies for CKD. In addition, these studies will further our knowledge of Wnt/?-catenin signaling and the role of FoxO in CKD.